This study is a multicenter, double-blind, randomized, placebo-controlled clinical trial that will be conducted in 10 tertiary hospitals in China from October 2023 to October 2025. The 10 hospitals are the Shanghai Skin Diseases Hospital, the Third Hospital affiliated to Chongqing Medical University, the First Hospital of Hangzhou, the Third Hospital affiliated to Peking University, the First Hospital of Fujian Medical University, the Skin Diseases Hospital affiliated to South Medical University, the First Hospital of Wuhan, the First Hospital affiliated to Kunming Medical University, the Skin Diseases Hospital of Jiangxi, and the First Hospital affiliated to Anhui University of traditional Chinese medicine. In this study, patients with mild AD who provide signed informed consent will be randomly assigned (1:1) to a treatment group (HBL with CAPCS) and a control group (HBL without CAPCS, or placebo). This study is registered with the Chinese Clinical Trial Registry (ChiCTR2400087274).

In this study, the sample size was calculated based on the proportion of patients achieving at least 60% improvement (defined as the effective rate) in the Eczema Area and Severity Index (EASI) score from baseline to week 2 (EASI₆₀) in both the treatment group and the control group. A previous pilot study (data not published) indicated that the proportion of EASI₆₀ achievement at week 2 was 50% in the CAPCS group and 20% in the placebo group. In addition, a previous open-label clinical trial involving 60 pediatric patients with AD demonstrated comparable efficacy outcomes, with CAPCS combination therapy showing a 42.86% response rate versus 7.14% for the control group at week 2, with statistically significant differences (P<.05) [25]. In this study, we used the following formula to calculate the sample size:

We set the proportion of EASI₆₀ achievement at week 2 in the treatment group to p1=45%, the proportion of EASI₆₀ achievement at week 2 in the control group to p2=20%, the type I error to α=0.05, the type II error to β=0.1. The sample size calculation indicated that at least 70 patients be recruited in each group. Considering a 20% dropout rate and a 10% multicenter effect, we plan to enroll 100 patients with mild AD in each group, for a total of 200 patients with mild AD.

In this study, AD will be confirmed in accordance with Williams diagnostic criteria [26], and patients with AD will be recruited and screened from 10 tertiary hospitals in China from October 2023 to October 2025 by publishing recruitment announcements in newspapers or on information platforms of the hospital official websites, display boards outside the clinics, and information counters. All patients are required to sign informed consent forms before the study begins.

In this study, patients will be included if they meet the inclusion criteria as follows: (1) diagnosis of AD according to Williams diagnostic criteria, (2) age 18-55 years for both males and females, (3) a target lesion with a diameter of 2-10 cm located on the limbs or the trunk, (4) EASI score<6, and (5) skin area<5% body surface area before treatment. The exclusion criteria are as follows: (1) pregnant or lactating women; (2) patients who have undergone AD system treatment within 3 months or local treatment or phototherapy within the past 2 weeks at the time of recruitment; (3) patients with serious systemic diseases or disorders of the heart, lungs, liver, or kidneys or mental illness; (4) patients who are allergic to calcium supplements; (5) patients with systemic disease or an active skin condition (eg, psoriasis) that affects the evaluation; (6) patients with scars, birthmarks, tattoos, freckles, etc; (7) patients with bacterial, viral, or fungal infections requiring anti-infective therapy; (8) patients who have participated or are currently participating in clinical trials of other drugs within the past month; and (9) patients with communication barriers, unable to complete the questionnaire.

In this study, the block randomization method with a random combination of block lengths 4 and 6 will be used to assign the 200 patients with mild AD (1:1) to the treatment group (HBL with CAPCS; n=100, 50%) and the control group (HBL without CAPCS, placebo; n=100, 50%). Independent statisticians will use the entire randomization feature of SAS (SAS Institute) to construct 200 unique computer-generated random sequences for subsequent block randomization. The random numbers printed for participants will be placed in a light-resistant envelope and managed by a third party (not the investigators). If a patient is eligible after the baseline assessment and has provided informed consent, the clinical research coordinator will call the third party to obtain the patient’s random number and finish the group assignment. Next, a dermatologist will administer the corresponding intervention to the patient.

In this study, both patients with mild AD and dermatologists (investigators) will be blinded to the treatment allocation. Furthermore, the outcome assessors, data collectors, and statistician responsible for data analysis will also be unaware of the group assignment during the trial period to prevent bias.

According to the Declaration of Helsinki, all participants will be respected and can withdraw from the study at any time for any reason. The personal information about participants will be collected and kept confidential. In this study, patients can withdraw at any time, and the reason for withdrawal will be recorded in the CRF.

This study was reviewed and approved by the Ethics Committee of Shanghai Dermatology Hospital and the Institutional Ethics Review Committee of the Shanghai Skin Diseases Hospital in 2023 (approval number 2023-33). The implementation of the study will strictly adhere to the Declaration of Helsinki. Any adverse events, violations, and amendments to the study protocol or informed consent form will be reported to the Ethics Committee of the Shanghai Skin Diseases Hospital. All patients will sign the informed consent form before enrollment, and participant information will be protected.

In this study, we will implement a series of measures to improve data quality and ensure the reliability of collected data. First, we will implement a pilot study to train all investigators participating in this study and to evaluate the reliability and validity of the CRF used for data collection. Second, we will assign two PhD students as the inspectors to conduct comprehensive checks in order to ensure the accuracy and integrity of the collected data. Third, we will actively contact all recruited patients during the 4 weeks of follow-up because frequent communication will enhance the patients’ trust and thereby increase their willingness to participate and remain in the study.

In this study, all data will be recorded in the CRF and then input into a database established using Epidata 3.1 software. The full analysis set (FAS) and the per protocol set (PPS) will be analyzed using the SAS 9.2 statistical package, and missing data will be processed using the multiple imputation method. In this study, quantitative variables with a normal distribution will be expressed as means (SDs), while quantitative variables with a skewed distribution will be expressed as medians (IQRs). Qualitative variables will be expressed as frequency counts and proportions (%). We will apply the 2-sample Student t test or the Wilcoxon rank-sum test to examine differences between groups for quantitative variables, as appropriate, and repeated measurement data will be analyzed using repeated-measure ANOVA. The Wilcoxon rank-sum test, the chi-square test, or the Fisher exact test will be performed to examine the differences between groups for qualitative variables, as appropriate. In this study, P<.05 (2-tailed) will be considered statistically significant.

AD is an autoimmune inflammatory skin disease that can last for a lifetime [33]. AD usually exhibits a chronic course, with thickening of the skin, sleep disturbance, severe life quality interference, and daily activity deprivation, which not only causes physical pain for the patient but also imposes heavy social and economic burdens on them [34,35]. For AD treatment, anti-inflammatory agents, wet-wrap therapy, systemic immunosuppressants, and short-term steroid treatment are used to manage persistent or severe AD cases [11]. However, the use of local and systematic treatment often fails to provide long-term disease control due to safety concerns. As adjuvant therapy, the external application of moisturizing emollients is the basis for AD treatment, which can not only improve the hydration of the cuticle and reduce inflammation [15] but also repair the damaged skin barrier, decrease the stimulation of external factors, and reduce the attack frequency and disease severity [16]. In recent years, the development of new active ingredients has led to the widespread clinical application of emollients to improve the skin barrier in patients with AD.

CAPCS, as new active ingredients, are derived from farmed marine shellfish. Previous studies indicate that the active calcium in CAPCS can inhibit the release of inflammatory mediators and exhibit anti-inflammatory and anti-allergic properties. Moreover, HBL incorporated with CAPCS has similar therapeutic effects as desonide cream in scratch control and itching alleviation in mice and in patients with AD [21], but there is a lack of high-quality clinical trial evidence. This protocol outlines the basic principle and design of a multicenter, double blind, randomized, placebo-controlled trial with 200 patients with mild AD in China. We plan to evaluate the treatment efficacy and safety of HBL incorporated with CAPCS in the enrolled patients, which is expected to yield more generalizable evidence due to the diversity in geography, climate, and participants from the 10 selected hospitals. To the best of our knowledge, this is the first multicenter clinical trial that will recruit 200 patients with AD to evaluate the treatment efficacy and safety of HBL incorporated with CAPCS in China. The clinical data of patients with AD will be extracted from the health information system (HIS) directly without recall bias, resulting in high data quality.

This study may have a few limitations. First, the study period is set to 4 weeks, which limits the observation of the long-term effects of HBL incorporated with CAPCS, as well as its efficacy in prevention of disease recurrence in patients with AD. Second, differences in climate (temperature, humidity, ultraviolet radiation, seasonal changes), lifestyle habits (high-fat food consumption, high-calorie diets, tobacco smoking, alcohol drinking) and other extrinsic factors (cultural differences, occupational exposure, etc) in the 10 selected hospitals may cause information bias, which should be adjusted through sensitivity analysis and subgroup analysis. Third, patients in this study will be instructed not to use any additional treatment for AD, which might induce a relatively high rate of withdrawal in them.

This study is expected to confirm that the application of HBL incorporated with CAPCS can relieve itching, control scratching, and improve the skin barrier with reparative, anti-inflammatory, and moisturizing effects. If the treatment efficacy is proven, HBL incorporated with CAPCS could be clinically used as an adjunctive therapy in ameliorating mild AD.